Aldose reductase (AR) is a monomeric (α/β)8-barrel (TIM barrel) protein belonging to the aldo-keto reductase (AKR) superfamily (Jez et al. (1997) Biochem. J. 326: 625-636; Rondeau et al. (1992) Nature 355:469-72; Wilson et al. (1992) Science 257:81-84). Aldose reductase is a broad-specificity oxidoreductase catalyzing the reduction of a structurally-diverse range of aldehydes, including medium to long chain aldehydes, glucose and other aldo-sugars, aldehyde metabolites of neurotransmitters, isocorticosteroid hormones, and a variety of xenobiotic aldehydes to their corresponding alcohols (Bhatnagar et al. (1992) Biochem. Med. Metab. Biol. 48:91-121). Reduction of glucose to sorbitol by aldose reductase constitutes the first and rate-limiting step of the polyol pathway that converts glucose to fructose via sorbitol dehydrogenase. Although this pathway usually represents a minor route of glucose metabolism, its activation during diabetes has been linked to the development of several clinically significant secondary complications such as nephropathy, neuropathy, retinopathy and cardiovascular related complications (Bhatnagar et al. (1992) Biochem. Med. Metab. Biol. 48:91-121; Nishikawa et al. (2000) Kidney Int. Suppl. 77:S26-30). Several drugs that inhibit aldose reductase have been shown to prevent hyperglycemia-induced changes in nerve, kidney, and lens of experimental animals, although clinical trials with Type I and Type II diabetics have not been uniformly positive (Bhatnagar et al. (1992) Biochem. Med. Metab. Biol. 48:91-121; Nishikawa et al. (2000) Kidney Int. Suppl. 77:S26-30; Parry (1999) Am J Med 107:27S-33S).
In addition to glucose, it has been shown that aldose reductase catalyzes the reduction of multiple biologically-active aldehydes generated by the peroxidation of membrane lipids and lipoproteins (Srivastava et al. (1995) Biochem. Biophys. Res. Commun. 217:741-746; Srivastava et al. (1998) Biochem. J. 329:469-475; Srivastava et al. (1999) Biochemistry 38:42-54) or during glucose (van der Jagt et al. (1992) J. Biol. Chem. 267:4364-4369) and amine (Kawamura et al. (1999) Biochem Pharmacol 58:517-24) metabolism. The aldehyde-detoxifying role of aldose reductase is supported by the observation that inhibition of the enzyme increases the accumulation of lipid peroxidation products (Rittner et al. (1999) J Clin Invest 103:1007-13; Shinmura et al. (2002) Circ Res 91:240-612) that cause cytotoxicity (Ruef et al. (2000) Arterioscler Thromb Vase Biol 20:1745-52; Ramana et al. (2002) J Biol Chem 277(35):32063-70). The most abundant and toxic lipid peroxidation product is 4-hydroxy-trans-2-nonenal (16) which is efficiently reduced by aldose reductase in vitro and in vivo.